CYLD inhibits melanoma growth and progression through suppression of the jnk/ap-1 and β1-integrin signaling pathways

Hengning Ke, Christina K. Augustine, Vineela D. Gandham, Jane Y. Jin, Douglas S. Tyler, Steven K. Akiyama, Russell P. Hall, Jennifer Y. Zhang

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The molecular mechanisms mediating cylindromatosis (CYLD) tumor suppressor function appear to be manifold. Here, we demonstrate that, in contrast to the increased levels of phosphorylated c-Jun NH 2 -terminal kinase (pJNK), CYLD was decreased in a majority of the melanoma cell lines and tissues examined. Exogenous expression of CYLD but not its catalytically deficient mutant markedly inhibited melanoma cell proliferation and migration in vitro and subcutaneous tumor growth in vivo. In addition, the melanoma cells expressing exogenous CYLD were unable to form pulmonary tumor nodules following tail-vein injection. At the molecular level, CYLD decreased β1-integrin and inhibited pJNK induction by tumor necrosis factor-α or cell attachment to collagen IV. Moreover, CYLD induced an array of other molecular changes associated with modulation of the "malignant" phenotype, including a decreased expression of cyclin D1, N-cadherin, and nuclear Bcl3, and an increased expression of p53 and E-cadherin. Most interestingly, coexpression of the constitutively active MKK7 or c-Jun mutants with CYLD prevented the above molecular changes, and fully restored melanoma growth and metastatic potential in vivo. Our findings demonstrate that the JNK/activator protein 1 signaling pathway underlies the melanoma growth and metastasis that are associated with CYLD loss of function. Thus, restoration of CYLD and inhibition of JNK and β1-integrin function represent potential therapeutic strategies for treatment of malignant melanoma.

Original languageEnglish (US)
Pages (from-to)221-229
Number of pages9
JournalJournal of Investigative Dermatology
Volume133
Issue number1
DOIs
StatePublished - Jan 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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